If DNA could adopt only the structure of DNA with which we are most familiar - the canonical B-form double helix - it would be devoid of biologic function. The ability of proteins to coerce DNA into a variety of non-canonical structures is an absolute prerequisite for many of the most important processing events that take place on the genome, including replication, transcription initiation, DNA repair, recombination, and packaging into chromatin. The long-term goals of this project are to gain a molecular-level understanding of protein/DNA interactions, with a particular focus on the role of DNA distortion in genome function. The specific systems chosen for study are: DNA glycosylases. These enzymes initiate the repair of mutagenic base lesions residues in DNA. How the enzymes distinguish their cognate lesions from the vast excess of normal DNA is a subject of the proposed investigation. Topoisomerase II. Type II topoisomerases (Topo ll's) serve important roles in maintaining the superhelical state of the genome and in decatenating chromosomes during cell division. Topo ll's are the targets of some of the most important drugs used to treat cancer and bacterial infections. The proposed studies will focus on understanding the mechanisms of these enzymes and the drugs that target them. DNA mismatch recognition proteins. The MutS family of proteins is responsible for recognizing mismatched base-pairs in DNA, and is clearly implicated in protection from cancer. Our studies will focus on understanding how these proteins locate rare mismatches embedded in a sea of normally paired DNA. DNA cytosine methyltransferases. These enzymes add crucial information content to the genome by catalyzing the formation of a fifth nucleobase, 5-methylcytosine. Our studies will focus on understanding how DNA cytosine methyltransferases (DCMTases) target particular cytosine residues in DNA for extrusion from the DNA helix and insert them into the extrahelical active site on the enzyme.